There are no randomized clinical trials of Legalon SIL or silibinin in the treatment of amatoxin induced mushroom poisoning. Evidence for its use comes from observational studies in humans, a variety of animal studies with mixed results, and in vitro studies in cultured human hepatocytes.
Although in an experimental model of cultured canine hepatocytes silibinin was not able to reduce cytotoxicity, two experiments using cultured human hepatocytes demonstrated that the addition of silibinin was able to protect against lipid peroxidation and cytotoxicity, and also stimulate cell proliferation and attachment.5, 6, and 7
One of the earliest animal studies was conducted in mice using sublethal doses of Amanita phalloides extract administered intraperitoneally (IP) every 24 hours for 3 doses.2 Silymarin was administered intravenously (IV) at 16 and 24 hours, with the highest dose resulting in a 58% survival compared to 11% in the control group. When the experiment was repeated using a purified α-amatoxin, time was the most important factor in predicting survival. All of the mice treated with silymarin one hour before exposure survived, while none survived when treatment was started 8 hours after exposure.2 A similar study in mice treated with IP α-amatoxin followed 4 hours later with IP silibinin dosed every 4 to 6 hours for 48 hours was not able to show a benefit in reducing the increase in LFTs or a difference in the liver histopathology.11
A study conducted in canines utilized an oral sublethal dose of Amanita phalloides extract and IV silymarin administered at 5 and 24 hours postingestion. Silymarin prevented or reduced the elevation in LFTs and the fall in clotting factors and reduced the severity of liver failure.3 A similar protocol, but this time using silibinin instead of silymarin, demonstrated similar biochemical findings and a 100% survival.12
A 20 year retrospective review of European and American case reports of over 2000 hospitalized patients with amatoxin induced mushroom poisoning concluded that silibinin alone, or in combination, and N-acetylcysteine show the most promise as hepatoprotective therapies.1 The authors acknowledged the difficulty in determining efficacy of various therapies given the lack of randomized controlled trials. A more recent review included the data from the previous authors and any subsequent hospitalized patients in the interim. A multidimensional multivariate statistical analysis of the data reached a similar conclusion.9
A retrospective case series of Amanita phalloides poisoning from Australia and New South Wales included 10 patients with probable poisoning, 9 of whom were treated with silibinin since use began in 2005.10 Four of these patients died. Mistaken identity of the mushrooms, particularly in immigrants, and a large number of ingested mushrooms seemed associated with a higher mortality. There was often a time delay to administration of Legalon SIL due to stocking and acquisition issues.